Process for production of cyclic diamine compounds or salts thereof

ABSTRACT

The present invention is directed to a process for producing cyclic diamine compounds (4) or salts or intermediates thereof according to the following reaction scheme:  
                 
(wherein R is a protective group and Ar is an optionally substituted aryl group). According to the present invention, the cyclic diamine compounds (4) useful as drugs or salts or intermediates thereof can be produced at high levels of yield and purity in terms of industrially advantageous productivity.

TECHNICAL FIELD

The present invention relates to a process for production of cyclicdiamine compounds or salts thereof serving as an ACAT inhibitor, as wellas intermediates thereof.

BACKGROUND ART

Acyl-Coenzyme A cholesterol acyltransferase (ACAT) is an enzyme that iscapable of catalyzing synthesis of a cholesterol ester from cholesteroland plays an important role in the metabolism and absorption ofcholesterol in the gastrointestinal tract.

In recent years, it has been reported that the plasma cholesterol levelcan be effectively suppressed by controlling the activity of ACATpresent in the small intestine and the liver. So far, a number ofstudies have been carried out for ACAT inhibitors.

Meanwhile, the present inventors focused on ACAT in vascular wall andstudied on the selective inhibitors against this type of ACAT. As aresult, it was found that among azole compounds having a cyclic diaminestructure, cyclic diamine compounds represented by the following formula(4):

(wherein Ar represents an aryl group which may have a substituent(s))were useful as therapeutic drugs for hyperlipidemia andarteriosclerosis, having less side effect and excellent oral absorptionproperty. Based on such findings, the present inventors filed aninternational patent application (WO 98/54153).

In the above patent application, the compound (4) can be producedthrough the 5-step process of reactions as described below:

(wherein Ar has the same meaning as defined above).

According to this reaction process, transformation of alcohol of thecompound (1a) having an amino group protected by a tert-butoxy carbonylgroup (Boc) into thioether is performed by a method in which thehydroxyl group is transformed to a methanesulfonyloxy group whichreadily leaves, followed by reacting with 2-mercaptobenzimidazole in thepresence of a base. However, since the compound (1b) having such aleaving group has poor stability, by-products and decomposed productsfrom the compound (1b) are readily generated during removal of thesolvent included in post treatment of a large scale synthesis. As aresult, it is difficult to avoid problems such as requirement ofcumbersome purification procedures and variation in yield.

An object of the present invention is to provide an industriallyadvantageous process for producing a compound (4) serving as an ACATinhibitor or a salt thereof. Another object of the invention is toprovide a process for producing an intermediate therefor or a saltthereof.

DISCLOSURE OF THE INVENTION

In view of the foregoing, the present inventors have carried outextensive studies, and have found that a compound (4) or a salt thereofcan be effectively and shortly produced at high levels of yield andpurity when the reaction was carried out using a phosphine reagent or aphosphonium ylide reagent needed to transform alcohol into thioether, asshown in the reaction scheme below:

(wherein R represents a protective group and Ar represents an aryl groupwhich may have a substituent(s)). The present invention has beenaccomplished on the basis of this finding.

Accordingly, the present invention provides a process for producing acompound (2), characterized in that the process comprises reacting theaforementioned compound (1) with 2-mercaptobenzimidazole orbis(2-benzimidazolyl)disulfide in the presence of a phosphine reagent ora phosphonium ylide reagent. The invention also provides a process forproducing a compound (3) or a salt thereof, characterized in that theprocess comprises removing a protective group of the compound (2).

The present invention also provides a process for producing a cyclicdiamine compound (4), characterized in that the process comprisesreacting the aforementioned compound (1) with 2-mercaptobenzimidazole orbis(2-benzimidazolyl)disulfide in the presence of a phosphine reagent ora phosphonium ylide reagent, to thereby form a compound (2), removing aprotective group from the compound (2), to thereby form a compound (3)or a salt thereof, and reacting a compound (5).

The present invention also provides1-formyl-4-[2-(benzimidazol-2-ylthio)ethyl]piperazine represented by thefollowing formula (6).

BEST MODE FOR CARRYING OUT THE INVENTION

With regard to compounds (1) and (2) of the present invention, examplesof the protective group represented by “R” include amide-type protectivegroups such as formyl, acetyl, chloroacetyl, trichloroacetyl,trifluoroacetyl, phenylacetyl, 3-pyridylcarbonyl, benzoyl, and4-phenylbenzoyl; urethane-type protective groups such asmethoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl,4-methoxybenzyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl,2-trimethylsilylethyloxycarbonyl, 2-phenylethyloxycarbonyl,tert-butoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, and9-fluorenylmethoxycarbonyl; allyl-type protective groups such as allyland crotyl; and benzyl-type protective groups such as benzyl and4-methoxybenzyl. Of these, a formyl group, an acetyl group, and atert-butoxycarbonyl group are preferred, with a formyl group beingparticularly preferred.

Examples of the aryl moiety of the aryl group which may have asubstituent contained in compounds (4) and (5) include 6-memberedaromatic hydrocarbon groups and 5 to 7 membered heterocyclic groupshaving as a heteroatom(s) 1 to 3 nitrogen atoms. Specific examples ofpreferred groups include a phenyl group, a pyridyl group, and apyrimidyl group. Examples of the substituent include a lower alkylgroup, a lower alkoxy group, a lower alkoxy-lower alkoxy group, a loweralkanoyloxy group, a lower alkoxycarbonyl-lower alkoxy group, a loweralkylsulfonyloxy group, a di-lower alkoxyphosphoryloxy group, a di-loweralkylamino group, a lower alkylthio group, a lower alkylsulfinyl group,a lower alkylsulfonyl group, a hydroxyl group, and a nitro group. Theterm “lower” refers to a number of carbon atoms of 1 to 6, and the alkylmoiety may be linear or branched. The following are some examples ofpreferred substituents. For the lower alkyl group, methyl, ethyl,n-propyl, isopropyl, and tert-butyl; for the lower alkoxy group,methoxy, ethoxy, and n-propoxy; for the lower alkoxy-lower alkoxy group,methoxymethoxy, ethoxymethoxy, and ethoxyethoxy; for the loweralkanoyloxy group, acetyloxy and propionyloxy; for the loweralkoxycarbonyl-lower alkoxy group, ethoxycarbonylmethoxy; for the loweralkylsulfonyloxy group, methylsulfonyloxy; for the di-loweralkoxyphosphoryloxy group, dimethoxyphosphoryloxyl for the di-loweralkylamino group, dimethylamino and diethylamino; for the loweralkylthio group, methylthio, ethylthio, and isopropylthio; for the loweralkylsulfinyl group, methylsulfinyl, ethylsulfinyl, andisopropylsulfinyl; and for the lower alkylsulfonyl group,methylsulfonyl, ethylsulfonyl, and isopropylsulfonyl.

Compounds (3) and (4) of the present invention may be converted to thecorresponding acid-added salts. Examples of the salts include inorganicacid salts such as hydrochlorides, sulfates, nitrates, and phosphates;and organic acid salts such as methanesulfonates, maleates, fumarates,citrates, tartrates, and malates.

Compound (4) may be a non-solvated species or a hydrate or a solvatedspecies formed from a solvent employed in production or purificationsuch as water and alcohol.

According to the present invention, compound (2) is produced fromcompound (1) by use of 2-mercaptobenzimidazole orbis(2-benzimidazolyl)disulfide in the presence of a phosphine reagent ora phosphonium ylide reagent. Examples of preferred modes include [1] amethod including reacting compound (1) with 2-mercaptobenzimidazole inthe presence of a phosphine reagent and an azo reagent or anethylenedicarboxylic acid reagent such as dimethyl maleate orN,N,N′,N′-tetramethylfumaramide (Method A), [2] a method includingreacting compound (1) with bis(2-benzimidazolyl) disulfide in thepresence of a phosphine reagent (Method B), and [3] a method includingreacting compound (1) with 2-mercaptobenzimidazole in the presence of aphosphonium ylide reagent (Method C).

<Method A>

In Method A, a compound (1), 2-mercaptobenzimidazole, and a phosphinereagent are dissolved in a reaction solvent, and an azo reagent or anethylenedicarboxylic acid reagent is added to the solution. The mixtureis allowed to react under an argon or nitrogen atomosphere, at 0° C. to100° C., preferably at room temperature to 80° C., for 2 hours to 24hours.

Examples of phosphine reagents which are useful in the reaction includetrialkylphosphines such as trimethylphosphine, triethylphosphine,tripropylphosphine, triisopropylphosphine, tributylphosphine,triisobutylphosphine, and tricyclohexylphosphine; and triarylphosphinessuch as triphenylphosphine and diphenylphosphinopolystyrene. Of these,trimethylphosphine, tributylphosphine, and triphenylphosphine arepreferred.

Examples of the azo reagent include diethyl azodicarbosylate (DEAD),1,1′-azobis(N,N-dimethylformamide) (TMAD),1,1′-(azodicarbonyl)dipiperidine (ADDP),1,1′-azobis(N,N-diisopropylformamide) (TIPA), and1,6-dimethyl-1,5,7-hexahydro-1,4,6,7-tetrazocine-2,5-dione (DHTD). Ofthese, diethyl azodicarbosylate is particularly preferred.

Examples of the reaction solvent include dimethylformamide,tetrahydrofuran, dioxane, acetonitrile, nitromethane, acetone, ethylacetate, benzene, chlorobenzene, toluene, chloroform, and methylenechloride. Of these, dimethylformamide, tetrahydrofuran, dioxane, andacetonitrile are preferred, with dimethylformamide and tetrahydrofuranbeing particularly preferred.

<Method B>

In Method B, a compound (1), bis(2-benzimidazolyl)disulfide, and aphosphine reagent are dissolved in a solvent which is similar to thoseas recited in relation to method A, and the solution is allowed to reactunder an argon or nitrogen atmosphere, at room temperature to 100° C.,preferably 60° C. to 100° C., for 2 hours to 48 hours.

The phosphine reagent employed in the reaction is trialkylphosphine ortriarylphosphine as shown in Method A. Specific examples includetrimethylphosphine, triethylphosphine, tripropylphosphine,triisopropylphosphine, tributylphosphine, triisobutylphosphine,tricyclohexylphosphine, triphenylphosphine, anddiphenylphosphinopolystyrene. Of these, trimethylphosphine,tributylphosphine, and triphenylphosphine are preferred, withtrimethylphosphine being particularly preferred.

<Method C>

In Method C, a compound (1), 2-mercaptobenzimidazole, and a phosphoniumylide reagent are dissolved in a reaction solvent, and the solution isallowed to react under an argon or nitrogen atmosphere at roomtemperature to 120° C., preferably 80° C. to 100° C., for 2 hours to 12hours.

Examples of the phosphonium ylide reagent employable in the reactioninclude alkanoylmethylenetrialkylphosphorane,alkanoylmethylenetriarylphosphorane,alkoxycarbonylmethylenetrialkylphosphorane,alkoxycarbonylmethylenetriarylphosphorane,cyanomethylenetrialkylphosphorane, and cyanomethylenetriarylphosphorane.Examples of trialkyl include trimethyl, triethyl, tripropyl,triisopropyl, tributyl, triisobutyl, and tricyclohexyl, and examples oftriaryl include triphenyl and diphenylpolystyrene.

Alternatively, the reaction may be carried out by treating a compound(1) and 2-mercaptobenzimidazole with a phosphonium halide reagent in thepresence of a base, thereby forming a phosphonium ylide reagent in thereaction system.

Examples of the phosphonium halide reagent employable in the alternativemethod include (cyanomethyl)trialkylphosphonium halide,(cyanomethyl)triarylphosphonium halide,(alkylcarbonylmethyl)trialkylphosphonium halide,(alkylcarbonylmethyl)triarylphosphonium halide,(allyloxycarbonylmethyl)trialkylphosphonium halide, and(alkoxycarbonylmethyl)triarylphosphonium halide.

Notably, the aforementioned (cyanomethyl)trialkylphosphonium halide and(cyanomethyl)triarylphosphonium halide may be prepared by reacting thecorresponding halogenoacetonitrile with the correspondingtrialkylphosphine or triarylphosphine (Tetrahedron, vol. 57, p.5451-5454, 2001), and alkanoylmethylenetrialkylphosphorane or a similarcompound may be prepared by reacting the correspondingalkanoylhalomethyl or alkoxycarbonylhalomethyl with the correspondingtrialkylphosphine or triarylphosphine in a similar manner.

Examples of trialkylphosphine and triarylphosphine employed hereininclude the same compounds as shown in Method A. Of these,trimethylphosphine, tributylphosphine, and triphenylphosphine arepreferred, with trimethylphosphine being particularly preferred.

Examples of the aforementioned alkanoyl include formyl, acetyl,propionyl, and butyryl. Among them, acetyl, and propionyl are preferred.Examples of alkoxy in the alkoxycarbonyl include methoxy, ethoxy,propoxy, and butoxy. Of these, methoxy, ethoxy, and butoxy arepreferred.

As the halogen atom, chlorine, bromine, and iodine are preferred.

Examples of the base include organic bases such as triethylamine,N,N-diisopropylethylamine, 1,4-diazabicyclo[2,2,2]octane (DABCO),1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), and1,5-diazabicyclo[4,3,0]non-5-ene (DBN); and inorganic bases such aspotassium carbonate, sodium carbonate, cesium carbonate, lithiumcarbonate, lithium diisopropylamide, and potassium hexamethyldisilazide.Of these, N,N-diisopropylethylamine, potassium carbonate, lithiumdiisopropylamide, and potassium hexamethyldisilazide are preferred, withN,N-diisopropylethylamine and potassium carbonate being particularlypreferred.

Examples of preferred reaction solvents include dioxane,tetrahydrofuran, toluene, benzene, dimethylformamide, dimethylsulfoxide, acetonitrile, and propionitrile. Among them, propionitrile isparticularly preferred.

By removing the protective group of the thus-produced compound (2),1-[2-(benzimidazol-2-ylthio)ethyl]piperazine (compound (3)) or a saltthereof can be produced.

Deprotection reaction may be performed through any known deprotectionreaction (e.g., hydrolysis under acidic conditions by use ofhydrochloric acid or a similar acid, hydrolysis in the presence of analkali such as sodium hydroxide, hydrogenolysis, or reduction).

For example, an amide-type protective group can be removed by use of anacid such as hydrochloric acid, phosphoric acid, sulfuric acid, ortrifluoroacetic acid or an alkali such as sodium hydroxide or potassiumhydroxide, in a solvent such as methanol, ethanol, propanol,tetrahydrofuran, or dioxane or in a mixture of water and any of theaforementioned solvent generally at 0 to 100° C. A urethane-typeprotective group can be removed by use of an acid such as hydrochloricacid, phosphoric acid, sulfuric acid, or trifluoroacetic acid or areducing agent such as hydrogen-palladium, zinc, or sodium borohydride,in a solvent such as methanol, ethanol, propanol, tetrahydrofuran,dioxane, acetonitrile, or ethyl acetate generally at 0 to 100° C. Anallyl-type protective group can be removed by treating the compound witha complex such as a zirconium complex, a ruthenium complex, a palladiumcomplex, or an iridium complex, thereby isomerizing a vinyl group to thecorresponding enamine form, followed by hydrolysis. A benzyl-typeprotective group can be removed through hydrolysis in a solvent (e.g.;methanol or ethanol) in the presence of a catalyst (e.g.; palladium orplatinum).

A cyclic diamine compound (4) or a salt thereof can be produced byreacting a compound (3) or a salt thereof with a halogenoacetamidecompound (5).

The reaction may be performed through a known alkylation procedure.Specifically, the reaction may be performed in a solvent such asmethanol, ethanol, propanol, tetrahydrofuran, dioxane, acetone,acetonitrile, dimethylformamide, or dimethyl sulfoxide or in a mixtureof water and any of the aforementioned solvent in the presence of a basegenerally at 0 to 100° C.

Examples of the base employed in the alkylation include inorganic basessuch as alkali metal hydroxides (e.g., sodium hydroxide and potassiumhydroxide); alkali metal carbonates (e.g., sodium carbonate, potassiumcarbonate, and cesium carbonate); and alkali metal hydrogencarbonates(e.g., sodium hydrogencarbonate and potassium hydrogencarbonate); andorganic bases such as pyridine, triethylamine,N,N-diisopropylethylamine, N-methylmorpholine, N,N-dimethylaniline,DABCO, DBU, and DBN.

The halogen atom represented by Y is preferably a chlorine atom, abromine atom, or an iodine atom. Of these, a bromine atom isparticularly preferred.

Alternatively, compound (1) may be yielded through a known protectivegroup introducing reaction (see “PROTECTIVE GROUPS IN ORGANIC SYNTHESIS2nd Ed,” authored by THEODORA W. GREENE, PETER G. N. WUTS, JOHN WILEYSONS, INC). Specifically, compound (1) is produced by reacting aprotective group-introducing reagent for R with1-(2-hydroxyethyl)piperazine in the presence or absence of a base.

Examples of the amide-type protective group-introducing reagent includethe corresponding acyl halides, carboxylic anhydrides, carboxylates, andcarboxylate active esters. Examples of the urethane-type protectivegroup-introducing reagent include halogenated alkyl carbonates,halogenated aryl carbonates, halogenated aralkyl carbonates, activealkyl carbonates, active aryl carbonates, active aralkyl carbonates, andtert-butyl bicarbonate. Examples of the allyl-type protectivegroup-introducing reagent include the corresponding halogenated arylderivatives, and examples of the benzyl-type protectivegroup-introducing reagent include the corresponding halogenated benzylderivatives.

EXAMPLES

The present invention will next be described in more detail by way ofexamples.

Example 1 Production of1-formyl-4-[2-(benzimidazol-2-ylthio)ethyl]piperazine

To a solution containing 1-formyl-4-(2-hydroxyethyl)piperazine (1.58 g,10 mmol), 2-mercaptobenzimidazole (5.56 g, 37 mmol), andtriphenylphosphine (9.26 g, 35.3 mmol) in dimethylformamide (100 mL),diethyl azodicarboxylate (5.19 g, 29.8 mmol) was added dropwise over 5minutes with ice-cooling and stirring under argon. The mixture wasstirred for 80 minutes at room temperature, and then water (2 mL) wasadded to the mixture so as to deactivate the reagent. The reactionmixture was concentrated under reduced pressure, and chloroform (200 mL)was added to the residue. Insoluble material was removed throughfiltration, and the filtrate was concentrated under reduced pressure. 2NHydrochloric acid (20 mL) and ethyl acetate (100 mL) were added to theresidue, and the liquid was partitioned. The organic layer was extractedwith 2N hydrochloric acid (20 mL×2). The aqueous extract and the aqueouslayer were combined, and the mixture was washed with chloroform (50mL×2) . The pH of the mixture was adjusted to about 9 through additionof potassium carbonate, followed by extraction with chloroform (50mL×3), washing the organic layer with saturated brine, drying oversodium sulfate anhydrate, and removing the solvent. The thus-formedcrude product was crystallized from acetone-diethyl ether, therebyyielding 2.19 g of 1-formyl-4-[2-(benzimidazol-2-ylthio)ethyl]piperazine(yield: 76%) as a colorless crystalline powder. The crystallizationmother liquor was concentrated under reduced pressure, and the residuewas purified through silica gel column chromatography (eluent:chloroform:methanol=50:1 to 20:1), thereby yielding 0.42 g of1-formyl-4-[2-(benzimidazol-2-ylthio)ethyl]piperazine (yield: 14%) as acolorless crystalline powder. The overall yield was 90%.

Melting point: 146-148° C.

IR (KBr) cm⁻¹: 3440, 3049, 1619, 1441, 742.

¹H-NMR (CDCl₃) δ: 2.59 (2H, t, J=5.3 Hz), 2.63 (2H, t, J=5.3 Hz), 2.91(2H, t, J=6.1 Hz), 3.37 (2H, t, J=6.1 Hz), 3.46 (2H, t, J=5.0 Hz), 3.65(2H, t, J=5.0 Hz), 7.18 (1H, dd, J=7.3, 3.0 Hz), 7.21 (1H, dd, J=7.3,3.0 Hz), 7.41-7.58 (2H, m), 8.06 (1H, s).

MS (m/z): 290 (M⁺, 3.2), 140 (100).

Element analysis (as C₁₄H₁₈N₄OS) Calculated: C, 57.91; H, 6.25; N,19.29; S, 11.04. Found: C, 57.78; H, 6.30; N, 19.12; S, 11.15.

Example 2 Production of1-formyl-4-[2-(benzimidazol-2-ylthio)ethyl]piperazine

To a solution containing 1-formyl-4-(2-hydroxyethyl)piperazine (1.90 g,12 mmol), 2-mercaptobenzimidazole (1.50 g, 10 mmol), andN,N-diisopropylethylamine (1.80 g, 14 mmol) in propionitrile (16 mL),cyanomethyltrimethylphosphonium iodide (2.80 g, 11.5 mmol) was addedunder argon, and the mixture was refluxed for 2 hours. After cooling,the reaction mixture was poured into water (100 mL), and the liquid wassubjected to extraction with chloroform (100 mL×3) . The organic layerwas washed with saturated brine, followed by drying over sodium sulfateanhydrate and removing the solvent through filtration. The thus-formedcrude product was crystallized from acetone-diethyl ether, therebyyielding 2.50 g of 1-formyl-4-[2-(benzimidazol-2-ylthio)ethyl]piperazine(yield: 86%) as a colorless crystalline powder.

Example 3 Production of1-formyl-4-[2-(benzimidazol-2-ylthio)ethyl]piperazine

The procedure of Example 2 (reaction, treatment, and purificationthrough silica gel column chromatography) was repeated, except thatpotassium carbonate was used instead of N,N-diisopropylethylamine, tothereby yield 1-formyl-4-[2-(benzimidazol-2-ylthio)ethyllpiperazine(yield: 81%).

Example 4 Production of1-formyl-4-[2-(benzimidazol-2-ylthio)ethyl]piperazine

To a solution containing 1-formyl-4-(2-hydroxyethyl)piperazine (1.42 g,9.0 mmol) and bis(2-benzimidazolyl)disulfide (8.06 g, 27 mmol) inanhydrous pyridine (15 mL), tributylphosphine (5.46 g, 27 mmol) wasadded dropwise under argon, and then the mixture was stirred for 12hours at room temperature. The reaction mixture was concentrated underreduced pressure, and chloroform (100 mL) was added to the residue.Insoluble matter was removed through filtration, and the filtrate wasconcentrated. Subsequently, 2N hydrochloric acid (100 mL) and ethylacetate (100 mL) were added to the residue, and the organic layer waspartitioned. The organic layer was extracted with 2N hydrochloric acid(50 mL) and water (50 mL). The extract and the aqueous layer werecombined, and the mixture was washed with ethyl acetate (50 mL×2) . ThepH of the mixture was adjusted to about 10 through addition of sodiumcarbonate to the washed aqueous layer, followed by extraction withchloroform (100 mL, 50 mL×2), washing the organic layer with saturatedbrine, drying over sodium sulfate anhydrate, removing the solvent. Thethus-formed crude product was crystallized from acetone-diethyl ether,thereby yielding 1.50 g of1-formyl-4-[2-(benzimidazol-2-ylthio)ethyl]piperazine (yield: 57%) as acolorless crystalline powder.

Example 5 Production of 1-[2-(benzimidazol-2-ylthio)ethyl]piperazinetrihydrochloride

1-Formyl-4-[2-(benzimidazol-2-ylthio)ethyl]piperazine (1.45 g, 5.0 mmol)was dissolved in methanol (20 mL) . 12N Hydrochloric acid (2 mL) wasadded to the solution, and the mixture was stirred for 18 hours at roomtemperature. The reaction mixture was concentrated under reducedpressure, and the thus-formed solid material was crystallized fromchloroform-methanol, to thereby yield 1.67 g of1-[2-(benzimidazol-2-ylthio)ethyl]piperazine trihydrochloride (yield:90%) as a colorless crystalline powder.

Melting point: 241-246° C.

IR (KBr) cm⁻¹: 3374, 2938, 2647, 1630, 1522.

¹H-NMR (CDCl₃)δ: 3.37-3.50 (4H, m), 3.43-3.57 (4H, m), 3.54 (2H, t,J=7.0 Hz), 3.81 (2H, t, J=7.0 Hz), 7.31 (2H, dd, J=5.9, 3.3 Hz), 7.59(2H, dd, J=5.9, 3.3 Hz), 9.73 (2H, br s).

MS (m/z): 262 (M⁺-3HCl, 3.1), 140 (100).

Element analysis (C₁₃H₁₈N₄S.3HCl) Calculated: C, 42.00; H, 5.69; N,15.07. Found: C, 41.87; H, 5.62; N, 14.98.

Example 6 Production of2-[4-[2-(benzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide

1-[2-(Benzimidazol-2-ylthio)ethyl]piperazine trihydrochloride 1.0 g(2.69 mmol) was suspended in acetonitrile (30 mL), and potassiumcarbonate 1.45 g (10.49 mmol) was added to the suspension. Water (8 mL)was added dropwise to the mixture under stirring at room temperatureuntil the entirety of the suspension assumed a homogeneous solution.Subsequently,N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]-2-bromoacetamide 810 mg(2.52 mmol) was gradually added to the mixture, and the mixture wasstirred for 2.5 hours at room temperature. The reaction mixture wasdiluted with water (50 mL) and extracted with chloroform (100 mL×3). Theorganic layer was washed with saturated brine (50 mL), followed bydrying over sodium sulfate anhydrate and concentrating under reducedpressure. The residue was purified through silica gel columnchromatography (eluent: chloroform:saturated ammonia in methanol=20:1).The thus-obtained oily product was crystallized from ethanol-diethylether, thereby yielding 1.16 g of2-[4-[2-(benzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide(yield: 88%) as a colorless crystalline powder.

Melting point: 96-97° C.

IR (KBr) cm⁻¹: 3273, 1672, 1564, 1534, 1488.

¹H-NMR (CDCl₃)δ: 2.42 (3H, s), 2.50 (3H, s), 2.53 (3H, s), 2.71-3.05(10H, m), 3.23 (2H, t, J=5.4 Hz), 3.35 (2H, s), 6.68 (1H, s), 7.18-7.23(2H, m), 7.35-7.75 (2H, m), 8.43 (1H, br.s), 12.80 (1H, br.s).

MS (m/z): 502 (M⁺)

Element analysis as (C₂₃H₃₀N₆OS₃.1.2H₂O) Calculated: C, 52.68; H, 6.23;N, 16.03. Found: C, 52.63; H, 5.96; N, 15.82.

Example 7 Production of2-[4-[2-(benzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-(2,4,6-triisopropylphenyl)acetamide

The procedure of Example 6 (reaction and treatment) was repeated, exceptthat N-(2,4,6-triisopropylphenyl)-2-bromoacetamide was used instead ofN-[2,4-bis(methylthio)-6-methylpyridin-3-yl]-2-bromoacetamide, tothereby yield2-[4-[2-(benzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-(2,4,6-triisopropylphenyl)acetamide.

Example 8 Production of2-[4-[2-(benzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(isopropylthio)-6-methylpyridin-3-yl]acetamide

The procedure of Example 6 (reaction and treatment) was repeated, exceptthat N-[2,4-bis(isopropylthio)-6-methylpyridin-3-yl]-2-bromoacetamidewas used instead ofN-[2,4-bis(methylthio)-6-methylpyridin-3-yl]-2-bromoacetamide, tothereby yield2-[4-[2-(benzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(isopropylthio)-6-methylpyridin-3-yl]acetamide.

Industrial Applicability

According to the present invention, cyclic diamine compounds (4) usefulas drugs or salts or intermediates thereof can be produced at highlevels of yield and purity in terms of industrially advantageousproductivity.

1. A process for producing a compound represented by the followingformula (2):

(wherein R represents a protective group), characterized in that theprocess comprises reacting a compound represented by the followingformula (1):

(wherein R represents the same as mentioned above) with2-mercaptobenzimidazole or bis(2-benzimidazolyl)disulfide in thepresence of a phosphine reagent or a phosphonium ylide reagent.
 2. Aprocess for producing 1-[2-(benzimidazol-2-ylthio)ethyl]piperazinerepresented by the following formula (3):

or a salt thereof, characterized in that the process comprises reactinga compound represented by the following formula (1):

(wherein R represents a protective group) with 2-mercaptobenzimidazoleor bis(2-benzimidazolyl)disulfide in the presence of a phosphine reagentor a phosphonium ylide reagent, to thereby form a compound representedby the following formula (2):

(wherein R represents the same as mentioned above), and subsequently,removing the protective group.
 3. A process for producing cyclic diaminecompound represented by the following formula (4):

(wherein Ar represents an optionally substituted aryl group) or a saltthereof, characterized in that the process comprises reacting a compoundrepresented by the following formula (1):

(wherein R represents a protective group) with 2-mercaptobenzimidazoleor bis(2-benzimidazolyl) disulfide in the presence of a phosphinereagent or a phosphonium ylide reagent, to thereby form a compoundrepresented by the following formula (2):

(wherein R represents the same as mentioned above), subsequently,removing the protective group, to thereby form1-[2-(benzimidazol-2-ylthio)ethyl]piperazine represented by thefollowing formula (3):

or a salt thereof, and reacting the compound or a salt with ahalogenoacetamide compound represented by the following formula (5):

(wherein the Ar represents the same as mentioned above and Y representsa halogen atom).
 4. The process as described in any one of claims 1 to3, wherein the compound represented by formula (1) has been produced byreacting 4-(2-hydroxyethyl)piperazine with a reagent for introducingprotective group to an amino group.
 5. The process as described in anyone of claims 1 to 4, wherein R is a formyl group. 6.1-Formyl-4-[2-(benzimidazol-2-ylthio)ethyl]piperazine represented by thefollowing formula (6).